This invention relates generally to a method and system for use in quickly determining the causes and selecting an appropriate therapeutic treatment for peri-operative or non-surgical hemorrhaging in a patient having a compromised coagulation function or other coagulopathy. The present invention also relates to the field of medical diagnosis and treatment of patients with compromised coagulation function or other coagulopathy generally, and more particularly to the analysis of a patient's blood coagulation function and the influence coagulation promoting substances and/or coagulation inhibiting substances may have on that patient's blood coagulation function. The invention even more particularly relates to an apparatus and system for particularly selecting appropriate coagulation promoting substances for administration to a patient with compromised blood coagulation function as a therapeutic treatment for that patient or, alternatively for particularly selecting appropriate coagulation inhibiting substances for administration to a patient as an agent for inducing inhibition of clotting for that patient.
It is well known in the art to inhibit the coagulation of a patient's blood by administering various anticoagulant substances, such as, for example, heparin, to the blood, which compromises the patient's blood coagulation function (i.e., causes iatrogenic coagulopathy). Inhibiting the coagulation of blood in a patient is particularly useful during medical procedures which may, for example, utilize extracorporeal circulation, such as medical procedures including cardiovascular surgery and hemodialysis. After the medical procedure requiring compromised coagulation function is completed, it is then often desirable to restore coagulation function in the blood of the patient. Again, it is well known in the art to restore coagulation function in the blood of a patient having compromised coagulation function by administering known agents, such as, for example, protamine, that counteract the anticoagulant substance. An illustrative example of the appropriateness of the therapeutic use of an anticoagulation substance, followed by restoring proper coagulation function with an agent that counteracts the anticoagulation substance, follows.
A heart-lung machine is typically used during heart surgery for coronary artery bypass, valvular replacement or proximal aortic reconstruction. The heart-lung machine substitutes for the function of a patient's heart muscle to pump blood throughout the patient's body, and substitutes for lung function by removing carbon dioxide and adding oxygen to the patient's blood.
To use the heart-lung machine, inhibition of the coagulation cascade in the patient's blood is required in order to prevent clot formation on the interior surfaces of the heart-lung machine. In the coagulation cascade generally, fibrin formation is initiated by Factor XII, Prekallikrein and high molecular weight kininogen, or by Factor XI in the intrinsic coagulation pathway, or by release of "tissue factor" in the extrinsic coagulation pathway. The coagulation cascade ultimately results in the conversion of fibrinogen to fibrin.
The arrest or inhibition of the coagulation cascade in a patient's blood is typically accomplished by administering a coagulation inhibiting substance such as heparin to the patient. Heparin impedes coagulation by enhancing the effectiveness of anti-thrombin III, a naturally occurring substance in the blood which inhibits coagulation. Heparin inhibits proper coagulation function by causing a conformational change in anti-thrombin III that exposes additional factor binding sites on the anti-thrombin III molecule, which increases the ability of anti-thrombin III to bind with factors XIIa, XIa, IXa and Xa, which in turn reduces their ability to participate in the proper formation of fibrin. After the period of cardiopulmonary bypass is completed, the heparin effect is reversed by administering a heparin-antagonist agent, such as protamine.
Determining the proper number of units of heparin to be administered to a patient just prior to a medical procedure requiring compromised coagulation function is generally complicated because of two independent phenomena. First, the amount of heparin that must be injected into a patient to achieve a certain plasma heparin concentration varies from patient to patient due to an inherent difference in heparin potency and/or affinity of antithrombin III for heparin. Second, a given heparin level in a patient's plasma does not necessarily reflect an exact state of anticoagulation in that particular patient because of a number of factors peculiar to certain individual patients, such as extravascular depots, hemodilution, hypothermia, heparin resistance and anti-thrombin III deficiency.
Thus, it has been desirable to measure the coagulation function of a patient just prior to performance of the medical procedure. To determine whether the amount of heparin administered has effectively reduced the ability of the patient's blood to clot, typically the Activated Coagulation Time (ACT) is measured. The ACT was introduced by Hattersley in 1966 and is a method for the rapid determination of the Lee-White whole blood clotting time. Although initially performed by manual rotation of a test tube containing a patient's blood and a visual inspection for the presence of a clot, the ACT test is currently typically performed via an automated method performed by a machine known as the HEMOCHRON (International Technidyne, Edison, N.J.) or, the HEMOTEC device (Medtronic Blood Management, Parker, Colo.). Other devices and laboratory tests are also used to measure coagulation function.
As an example, with the HEMOCHRON device, typically a sample containing two (2) cc's of whole blood is withdrawn from the patient and placed in an ACT tube and the start time recorded. The tube is shaken to mix the blood with a diatomaceous powder which activates coagulation by its high surface area. The tube is also simultaneously warmed to normal body temperature, or 37.degree. C. A magnetic rod placed in the tube is observed by a magnetic detector, and when coagulation occurs, the rod is displaced, signaling completion of the test. This coagulation time, which is the elapsed time from the start of the test until coagulation is detected, is then recorded, and the difference between the coagulation time and the start time is known as the ACT time. A normal ACT has been described as taking from 100 to 140 seconds in a patient with normal coagulation function. However, significant inter-device and institutional factors may affect the results. Thus, it is common practice to establish a control, or normal ACT reading by testing the patient's blood before a medical procedure and before administration of a coagulation inhibiting substance.
The ACT is currently first measured prior to the medical procedure to provide this baseline control ACT or "normal ACT" and then is measured again after administration of heparin, or other coagulation inhibiting substance to document whether a safe level of anticoagulation has been attained. The ACT is also measured serially during the procedure or heart surgery, usually about every 30 minutes, to be sure that adequate anticoagulation is maintained since the heparin may normally be metabolized and/or excreted by the patient.
The ACT is also used after the procedure or heart surgery is completed. At this time, the heart has been restarted and is pumping blood through the lungs where oxygen is added to the blood and carbon dioxide is removed. Use of the heart-lung machine is completed and thus it becomes desirable to restore proper coagulation function to the patient.
The heparin anticoagulation effect is generally reversed by the administration of an antagonist to heparin, such as, for example, protamine. Protamine is polycationic and forms a complex with heparin, thus reversing heparin's effects on anti-thrombin III. After administering protamine, the ACT is measured to determine if the protamine has adequately reversed the effects of heparin. Thus, the ACT is run and the ACT time compared to the normal or baseline ACT time, which was measured prior to the operation.
Sometimes, however, the administration of protamine does not fully return the ACT to the normal or baseline condition. When this occurs, it is often the case that, in addition to an elevated ACT, the patient may also be experiencing uncontrolled bleeding as a result of the operation. Although many clinicians associate an increased ACT, and therefore, the cause of the patient's bleeding, with a prolonged heparin effect, the ACT is limited in that it is a test of essentially the entire coagulation cascade or system, and as such, it is affected by other changes in the coagulation cascade which may actually be responsible for the continued coagulopathy or compromised coagulation function indicated, in this case, both by the elevated ACT and by the uncontrolled bleeding of the patient. Therefore, an elevated ACT after heparin reversal with protamine does not necessarily indicate that residual (i.e., unneutralized) heparin is the cause of the elevated ACT. An elevated ACT can indicate a compromised coagulation function due to factors other than, or in addition to residual heparin. For example, hypothermia, decreased levels of fibronectin, destruction of, or abnormal function of serine protease (proteins required for blood to clot, otherwise known as clotting factors), hypofibrinogenemia, fibrinolysis and platelet abnormalities, both qualitative and quantitative, can influence the ACT and also be responsible for the compromised coagulation function responsible for the patient's bleeding.
Because of the many factors involved in the coagulation cascade and possible reasons for a patient's compromised coagulation function, there is a recognized need for tests which permit an analytical approach to diagnosis and treatment of compromised coagulation function. Typically, blood analysis laboratories test coagulation function in a patient's blood by using tests such as prothrombin time (PT), activated partial thromboplastin time (PPT) and platelet count (PLT). Unfortunately, the clinical utility of these tests is limited by the delay in obtaining results. There have been recent developments in instrumentation for on-sight testing which allows rapid return of results of coagulation function tests. Despotis, Santoro, et al. On Sight Prothrombin Time, Activated Partial Thromboplastin Time And Platelet Count, Anesthesiology 80:338-351, 1994, discuss using a panel of rapidly performed screening tests to delineate the etiology of compromised coagulation function in patients and conclude that the use of on sight coagulation tests can reduce blood product administration by more precisely determining what therapy to use. Unfortunately, even this protocol requires a number of different tests, each requiring expensive instrumentation, and each merely determining the general area of coagulation function that is abnormal, rather than determining an appropriate therapy. Furthermore, Gravlee, Arora, et al. Predictive Value Of Blood Count Clotting Test In Cardiac Surgical Patients, Ann Thorac. Surg., 58: 216-221, 1994 studied the same tests and concluded that "the predictive values of the tests are so low, it does not appear sensible to screen patients routinely using these clotting tests shortly after cardiopulmonary bypass."
As discusseed above, since an increased ACT is often associated with a prolonged heparin effect, clinicians may be inclined to administer an additional protamine dose when confronted with a bleeding patient and coupled with an elevated ACT. However, an elevated ACT, as discussed above, may not be due to residual heparin at all. In fact, an elevated, or increased ACT time after extracorporeal circulation may be due to any of the following etiologies: for instance, qualitative or quantitative abnormalities of platelets, factors I, II, V, VII, VIII, IX, X, XI, XII, Prekallikrein, high molecular weight kininogen, tissue factor, factor XIII, calcium ion deficiencies, and other etiologies such as fibrinolysis and disseminated intra-vascular coagulation (DIC) can all be implicated in abnormal coagulation. Each of these etiologies or factors may be implicated in one or more of the various stages of clot formation. Therefore, adding an additional dose of protamine may not successfully restore proper coagulation function in the patient. In fact, it is now increasingly more common to measure the patient's heparin level at the conclusion of the extracorporeal circulation procedure for determining the appropriate amount of protamine to use in the first instance for completely counteracting the remaining heparin.
One device currently used to assist in determining the appropriate protamine dose in order to completely counteract the heparin effect is the HEPCON (HemoTech Inc., Englewood, Colo.). The HEPCON device consists of four chambers which contain specific, generally increasing, amounts of protamine, thromboplastin and diluent. Air bubbles percolate through the blood sample in each chamber until a photocell detects clot formation in one of the chambers. Based upon the patient's height and weight, the device computes the proper amount of protamine needed to counteract the amount of heparin remaining in the patient's blood at the conclusion of the procedure. In essence, this device confirms whether or not a patient's bleeding tendency is due to excess heparin. If protamine administration is followed by obtaining an elevated ACT and a HEPCON test produces no shortening in clotting time between the baseline control sample and the samples with additional protamine added, this indicates that heparin is not circulating and it is likely that one or more other etiologies may be responsible for the compromised coagulation function and hemorrhaging.
As discussed above, bleeding in general, surgical or non-surgical patients, including those involved in cardiopulmonary bypass surgery where there is no longer any circulating heparin, may be due to a compromised coagulation function due to a decreased level or abnormal function of coagulation factors such as factors II, V, VII, VIII, IX, X, XI, XII, XIII, Prekallikrein, high molecular weight kininogen or tissue factor, and fibrinogen, as well as thrombocytopenia, abnormal platelet function, decreased levels of fibronectin, complement activation, fibrinolysis, disseminated intra-vascular coagulation or calcium ion deficiency. Decreased levels of serine proteases and platelets could be due to low grade coagulation which occurred during the extracorporeal circulation with attendant consumption of the factors and platelets used in forming clots, or damage and destruction sustained to blood cells when exposed to the surface of the heart-lung machine, and/or the oxygenator.
The anesthesiologist and surgeon are thus often faced with the situation that a patient is bleeding significantly and it is not due to excess heparin in the blood. A similar situation may occur in a patient with massive bleeding due to a medical etiology. Because of the numerous possibilities of which particular coagulation factor or combination of coagulation factors or other agents, such as, for example, platelets, calcium ion or pharmacologic agents are needed to restore the coagulation cascade and coagulation function and stem the hemorrhaging, combined with the extremely limited amount of time available, the patient is frequently treated with a "shotgun therapy," for example, by administration of many different coagulation promoting substances or other therapies at once, including, typically, the administration of platelets, fresh frozen plasma (FFP), and cryoprecipitate, and sometimes pharmacologic agents as well, such as desmopressin acetate (DDAVP) and sometimes epsilo-amino caproic acid (AMICAR). For example, Despotis, Santoro, et al. Prospective Evaluation And Clinical Utility Of On sight Monitoring Of Coagulation In Patients Undergoing Cardiac Operation, J. Thorac. Cardiovasc. Surg. 107:271-9, 1994, recognized that "because of the frequent absence of available laboratory data, standard treatment of microvascular bleeding after CPB is often non-specific (e.g., additional protamine, fresh frozen plasma, and platelet concentrates). In addition, hemostatic blood products are frequently administered on a prophylactic basis in an attempt to distinguish microvascular bleeding from surgical bleeding. Neither approach constitutes an optimal strategy for patient treatment."
Since the use of platelets, fresh frozen plasma and cryoprecipitate all carry the increased risk of disease transmission, a system to rapidly determine if one or two specific coagulation promoting therapies would be sufficient to restore coagulation function, would decrease the risk to the patient of contracting hepatitis, aids, and numerous other blood-borne diseases. Furthermore, in cases where it is determined that DDAVP or AMICAR, recombinant factors, or other pharmacologic agents would, by themselves be therapeutic, and would restore proper coagulation function, the patient would be spared transfusion of blood products altogether.
An additional reason to rapidly determine the specific appropriate therapy for restoring proper coagulation function is that as long as there is a compromised coagulation function or other deficiency in blood coagulation (i.e., a coagulopathy), the patient will require transfusion of more and more packed red blood cells (PRBCs). In addition to the increased risk of disease transmission, transfusion of large amounts of PRBCs dilutes the patient's existing coagulation factors and platelets in their blood, resulting in a condition know as "dilutional coagulopathy," thus possibly further compromising the coagulation function and contributing to the degree of hemorrhaging.
At present, complete, definitive coagulation function studies can only be done in the laboratory, which takes too long to be of use in determining a specific coagulation promoting substance to be used as a therapy against massive hemorrhage, whether under operating room or non-operating room conditions. There is thus a need for a method that is rapid enough to allow a doctor to determine and administer a specific coagulation promoting substance as a therapy for restoring proper coagulation function under the severe time constraints posed by an episode of rapid massive bleeding whether in the operating room or otherwise.
In addition, as discussed above in relation to disseminated intra-vascular coagulation or microvascular bleeding, certain post-operative coagulopathy is associated with depleted amounts or reduced functioning of platelets or coagulation factors. Since more complete inhibition of coagulation before instituting cardio-pulmonary bypass, or beginning any surgery associated with fibrinolysis (which includes non-bypass surgery, such as lengthy hip replacement surgery, and others), will provide an additional level of protection from destruction or reduction in amount or functioning of platelets or factors during cardio-pulmonary bypass or surgery associated with fibrinolysis, it is useful to be able to predict the most appropriate level of inhibition of coagulation which would best preserve platelets or factors so that they are available in the appropriate amounts and are functional to effect coagulation when cardiopulmonary bypass or surgery associated with fibrinolysis is completed.